Sapanisertib + Bevacizumab for Glioblastoma

Recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anti-epileptics, Herbal supplements

Disqualifiers: Concurrent malignancy, CNS metastases, Cardiac arrhythmia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 2

Duration: 28 days per cycle, up to 2 years

50 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires stopping certain medications before joining. You must stop using herbal supplements, non-traditional medications, and certain anti-coagulants before registration. If you're on enzyme-inducing anti-epileptic drugs, you need to stop them at least 10 days before starting the trial. Consult with the trial team about any other medications you are taking.

What data supports the effectiveness of the drug Bevacizumab for glioblastoma?

Bevacizumab has shown some benefits in treating glioblastoma, particularly in improving progression-free survival (the time during which the disease does not get worse) in patients whose cancer has returned after previous treatments. However, while it may improve quality of life, it has not been proven to extend overall survival. ^{1 2 3 4 5}

Is the combination of Sapanisertib and Bevacizumab safe for treating glioblastoma?

Bevacizumab, used in treating glioblastoma, can cause side effects like high blood pressure, bleeding, and blood clots, which can be serious. It is important to monitor for these side effects and manage them promptly. While Bevacizumab has been studied for safety, specific safety data for the combination with Sapanisertib is not provided in the available research. ^{3 6 7 8 9}

How is the drug Sapanisertib + Bevacizumab unique for treating glioblastoma?

The combination of Sapanisertib and Bevacizumab is unique because it targets both the growth of blood vessels that feed the tumor and the tumor cells themselves. Bevacizumab is known for its ability to block VEGF, a protein that promotes blood vessel growth, which is crucial for glioblastoma survival, while Sapanisertib may enhance this effect by inhibiting pathways that help tumor cells grow and survive. ^{2 3 6 10 11}

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of raptor/rictor-mammalian target of rapamycin (mTOR) (TORC1/2) inhibitor MLN0128 when given in combination with bevacizumab in treating patients with glioblastoma, a type of brain tumor, or a solid tumor that has spread and not responded to standard treatment. TORC1/2 inhibitor MLN0128 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the progression of tumors by blocking the growth of new blood vessels necessary for tumor growth.

Research Team

Lakshmi Nayak

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for adults with recurrent glioblastoma or advanced solid tumors that haven't responded to standard treatments. Participants must be able to swallow capsules, have no other concurrent cancers (except certain skin cancers), and use contraception if of child-bearing potential. They should not be on corticosteroids, pregnant, nursing, or have significant allergies to the drugs being tested.

Inclusion Criteria

Your blood and body chemistry need to be within certain limits.

I have a confirmed diagnosis of recurrent glioblastoma or an advanced cancer treatable with bevacizumab.

I have no other cancers except possibly treated skin cancer.

Exclusion Criteria

I have a stomach or intestine problem that affects how I absorb pills.

I haven't used specific growth factors recently.

I do not have uncontrolled high blood pressure, asthma, or diabetes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive TORC1/2 inhibitor MLN0128 orally once daily and bevacizumab intravenously on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle, up to 2 years

2 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up for 30 days and then annually thereafter.

30 days initially, then annually

Treatment Details

Interventions

• Bevacizumab
• MLN0128

Trial Overview The trial is testing a combination of TORC1/2 inhibitor MLN0128 and monoclonal antibody Bevacizumab in patients with specific types of brain and solid tumors. It aims to find the safest dose while assessing how these drugs might block tumor growth by inhibiting enzymes needed for cell growth and blood vessel formation.

Participant Groups

Group I: Treatment (TORC1/2 inhibitor INK128, bevacizumab) Experimental Treatment 4 Interventions

Patients receive TORC1/2 inhibitor INK128 PO QD on days 1-28 and bevacizumab IV on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a retrospective analysis of 123 patients with recurrent glioblastoma, those treated with bevacizumab showed significant improvements in both progression-free survival (PFS) and overall survival (OS) compared to a control group.

Older patients (55 years and above) and those with poorer performance status benefited the most from bevacizumab treatment, suggesting that age-related biological differences in glioblastoma may influence treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. Nghiemphu, PL., Liu, W., Lee, Y., et al.[2022]

Bevacizumab, a monoclonal antibody targeting VEGF, shows a meaningful increase in progression-free survival for newly diagnosed glioblastoma patients, but it does not improve overall survival, highlighting the need for further research.

In recurrent glioblastoma patients, while bevacizumab has shown improved radiographic response and progression-free survival in uncontrolled trials, its effect on overall survival is still being evaluated in an ongoing randomized phase III trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The future of antiangiogenic treatment in glioblastoma. Chinot, OL., Reardon, DA.[2015]

A study of 310 glioblastoma patients from 2010 to 2014 found that the use of bevacizumab did not improve overall survival compared to patients treated before its approval, with median survival remaining similar at 13.5 months for IDH wild-type tumors.

However, patients receiving bevacizumab experienced a significant reduction in corticosteroid use during second-line treatment, suggesting a potential clinical benefit in managing treatment side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab may improve quality of life, but not overall survival in glioblastoma: an epidemiological study. Gramatzki, D., Roth, P., Rushing, EJ., et al.[2020]

Bevacizumab, used to treat glioblastoma and other tumors, has a unique toxicity profile that can lead to serious side effects like gastrointestinal perforation and intracranial hemorrhages, particularly in glioblastoma patients.

The study systematically reviewed these adverse events, identifying risk factors and suggesting preventive and therapeutic measures to reduce treatment-related complications, emphasizing the need for careful monitoring in patients receiving this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical management of bevacizumab-related toxicities in glioblastoma. Brandes, AA., Bartolotti, M., Tosoni, A., et al.[2022]

Bevacizumab (Avastin) received accelerated FDA approval for treating glioblastoma multiforme (GBM) based on its ability to produce partial responses in 25.9% of patients in one trial and 19.6% in another, with median response durations of approximately 4.2 and 3.9 months, respectively.

While bevacizumab shows efficacy in GBM treatment, it is associated with significant adverse events, including serious risks like CNS hemorrhage and thromboembolic events, highlighting the need for careful patient monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Cohen, MH., Shen, YL., Keegan, P., et al.[2022]

Bevacizumab, a monoclonal antibody targeting VEGF, has shown improved patient outcomes in recurrent glioblastoma (GBM) when used in combination with chemotherapy, leading to its accelerated approval by the FDA based on positive results from phase 2 studies.

The treatment is associated with manageable toxicity, as severe adverse events occur in only a small percentage of patients, making it a safer option for those with recurrent GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab for the treatment of recurrent glioblastoma. Chamberlain, MC.[2023]

In a phase II clinical trial involving 158 patients with newly diagnosed glioblastoma, cediranib combined with radiation and temozolomide significantly improved 6-month progression-free survival (PFS) to 46.6% compared to 24.5% for the placebo group (P = 0.005).

Although cediranib showed efficacy in prolonging PFS, it was associated with a higher incidence of grade ≥3 adverse events compared to placebo (P = 0.02), and there was no significant difference in overall survival between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma. Batchelor, TT., Won, M., Chakravarti, A., et al.[2023]

Bevacizumab, a monoclonal antibody that targets VEGF, has shown promising results in treating recurrent glioblastoma multiforme (GBM), with notable response rates and progression-free survival at 6 months in various studies.

While early trials indicate that some patients may survive beyond 1 or 2 years on bevacizumab, definitive Phase III trial data are still needed to confirm its efficacy, and it is currently being tested in combination with other treatments for newly diagnosed GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab in glioblastoma multiforme. Specenier, P.[2015]

References

1. United States pubmed.ncbi.nlm.nih.gov

Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Bevacizumab in high-grade gliomas: past, present, and future. [2015]

3. England pubmed.ncbi.nlm.nih.gov

The future of antiangiogenic treatment in glioblastoma. [2015]

4. England pubmed.ncbi.nlm.nih.gov

Bevacizumab may improve quality of life, but not overall survival in glioblastoma: an epidemiological study. [2020]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Bevacizumab: in previously treated glioblastoma. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Bevacizumab combined with chemotherapy for glioblastoma: a meta-analysis of randomized controlled trials. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Practical management of bevacizumab-related toxicities in glioblastoma. [2022]

8. England pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Bevacizumab for the treatment of recurrent glioblastoma. [2023]

10. England pubmed.ncbi.nlm.nih.gov

NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Bevacizumab in glioblastoma multiforme. [2015]